Thromboxane ligands

ABSTRACT

A method of treating ocular hypotension, hypertension, hemorrhage, myocardial ischemia, angina pectoris, coronary contraction, cerebrovascular contraction after subarachnoidal hemorrhage, and asthma which comprises administering to a mammal suffering therefrom a therapeutically effective amount of a thromboxane ligand which is a compound formula I, ##STR1## wherein Y is (CH 2 ) x  ; Z is selected from the group consisting of O, OCH 2 , ##STR2## and (CR 2 ) x , x is an integer of 1 or 2; R 2  is hydrogen or an alkyl radical of from 1 to 4 carbons, A is an alkylene or alkenylene radical having from two to seven carbon atoms, which radical may be substituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxy groups or said alkylene or alkenylene may have one or more enchained oxo or imino radicals; B is a methyl radical or a cycloalkyl radical having from three to seven carbon atoms, or an aryl radical, selected from the group consisting of hydrocarbyl aryl and heteroaryl radicals wherein the heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, or substituted derivatives of said methyl, cycloalkyl or aryl radicals wherein said substituent is selected from the group consisting of halo, nitro, amino, thiol, hydroxy, alkyloxy and alkylcarboxy; and X is selected from the group consisting of cyano, --COOR, --CH 2  OR, --C(O)N(R 2 ), --CH 2  N(R 2 ) --CH═N--OH and --CH 2  SR 1  radicals wherein R is hydrogen or a C 1  to C 10  alkyl, phenyl or benzyl and E is O or S; or a pharmaceutically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of 08/926,662, filed Sep. 9, 1997,now U.S. Pat. No. 6,017,953; which is a continuation-in-part of U.S.patent application Ser. No. 08/832,431, filed on Apr. 2, 1997, now U.S.Pat. No. 5,741,812; which is a continuation in part of U.S. patentapplication Ser. No. 08/645,467, filed on May 13, 1996, now U.S. Pat.No. 5,650,431; which is a continuation in part of U.S. patentapplication Ser. No. 08/378,414, filed Jan. 26, 1995, now U.S. Pat. No.5,516,791; which is a division of U.S. patent application Ser. No.08/174,534, filed Dec. 28, 1993, now U.S. Pat. No. 5,416,106.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to thromboxane receptor ligands includinga carboxylic acid group derivative, which do not cause blood clotting.In particular, the thromboxane receptor ligands are bicyclic carboxylicacid and derivatives thereof wherein said bicyclic rings may behydrocarbyl or oxohydrocarbyl, e.g. 7-[carboxyalkyl or alkenyl]-6-[alkylor alkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octanes and derivativesthereof. In particular, ester, hydroxyl, amino, amido, azido, oxime,thiol, ether and thiol ether derivatives of said carboxylic acid groupare contemplated. In particular,7-[6-carboxy-2-hexenyl]-6-[3-hydroxy-1-octenyl]3-oxo-2,4-dioxobicyclo-[3.2.1]octane derivatives are disclosed. Thesecompounds are useful as thromboxane agonists and antagonists. Thesecompounds are also useful as ocular hypotensives.

2. Description of the Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupillary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Various U.S. Patents have recently issued which relate to thromboxaneligands and/or treating hemorrhaging. For example, U.S. Pat. Nos.5,128,322; 5,128,354; 5,149,540; 5,389,630; 5,415,863; 5,436,260;5,447,712; 5,482,960; 5,478,844 and 5,504,090 relate to methods oftreating hemorrhaging. U.S. Pat. Nos. 5,248,507; 5,264,220; 5,382,569;5,409,956; 5,443,848; 5,476,846; 5,480,645; 5,482,960 and 5,504,090relate to thromboxane ligands. It is thus clear that a great deal ofresearch is currently involved in thromboxane ligands, especially fortreating hemorrhaging and related conditions.

SUMMARY OF THE INVENTION

We have found that certain bicyclic carboxylic acids and derivativesthereof, wherein said bicyclic rings may be hydrocarbyl or oxyhydrocarbyl, e.g. 7-[carboxylalkyl or alkenyl]-6-[alkyl oralkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane derivatives thereof, e.g.ester, hydroxyl, amino, amido, azido, oxime, thiol, ether and thiolether derivatives of said carboxy group are potent ocular hypotensiveagents. We have further found that these compounds are thromboxaneligands and may have the unique ability, described herein, to mimic thevasoconstrictor properties of thromboxane A2 and its endoperoxideprecursors, without causing concomitant platelet aggregation, i.e. bloodclotting, and therefore said compounds provide a diverse variety ofmedical uses. Their potent vasoconstrictor properties may be safely usedin therapy as they do not cause the platelet aggregation and resultantthrombosis that would arise from using known thromboxane mimetics.

The vasoconstrictor properties would substantially reduce blood flow inblood vessels and could be used to prevent hemorrhaging associated withexternal or internal injuries without the risk of thrombosis. Thesecompounds may also be used as surgical adjuncts to reduce the bleedingfrom incisions at any anatomical location. Similarly, these compoundswould be useful in limiting the bleeding associated with toothextraction. The ability of these compounds to prevent hemorrhage,without causing platelet aggregation and resultant thrombosis, allowstheir safe application in systemic diseases where hemorrhage occurs. Forexample, bleeding from the gastro-intestinal tract associated withhemorrhoids, inflammatory bowel diseases, or gastric and peptic ulcermay be prevented. Bleeding associated with stroke may be prevented.Bleeding associated with stroke may be reduced without causingthrombosis and a potentially fatal complication. Bleeding is also afrequent complication in retinal diseases and surgeries resulting inimpaired vision. This would also be amenable to safe treatment by thevascular-selective thromboxane mimetics described herein. Excessivebleeding associated with menstruation, childbirth, and uterinedysfunction may also be safely treated.

The selective vasoconstrictor properties of these compounds may be usedto treat systemic hypotension. They may also be employed to restorenormal blood pressure in haemorragic, anaphylactic, or septic shockepisodes, without the serious risks associated with typical thromboxanemimetics which would result from their pro-aggregatory effects onplatelets.

The selective vasoconstrictor properties may also be used to providelocal anti-inflammatory effects in tissues such as the eye, skin, andnose. They may also be used to limit plasma exudation in burns andscalds.

A thromboxane-like vasoconstrictor that does not cause plateletaggregation may also be useful in optimizing blood born delivery ofdrugs and diagnostics in encapsulating vehicles. For example, deliveryof drugs or diagnostic substances encapsulated in heat-sensitive orlight-sensitive liposomes to the retina may be safely enhanced by agentsdescribed herein which selectively produce vasoconstriction.

Additionally, certain of the bicyclic carboxylic acid derivatives of thepresent invention are useful as thromboxane antagonists for treatingsystemic or pulmonary hypertension, myocardial ischemia, anginapectoris, coronary contraction, cerebrovascular contraction aftersubarachnoidal hemorrhage, cerebral hemorrhage and asthma.

Finally, the profound ocular hypotensive activity of these cycliccarbonate compounds is unexpected, given that the benchmarkthromboxane/endoperoxide mimetic U-46619 (Coleman, R. A., et.al., Br. J.Pharmacol. 73:773-778, 1981) causes ocular hypertension in primates. Thecompounds herein would, therefore, be useful for treating glaucoma andocular hypertension. They may be particularly useful as ocular surgicaladjuncts for preventing ocular hypertensive episodes and reducing localbleeding that may occur post-surgically without complications inherentin blood clotting.

The present invention relates to methods of treating ocular hypertensionand other diseases and conditions wherein thromboxane ligands are usefulfor treating which comprises administering an effective amount of abicyclic carboxylic acid derivative represented by the formula I##STR3## wherein Y is (CH₂)_(x), Z is selected from the group consistingof O, OCH₂, ##STR4## and (CR₂)_(x), x is an integer of 1 or 2, R₂ ishydrogen or an alkyl radical of from 1 to 4 carbons, e.g. methyl, orethyl;

A is an alkylene or alkenylene radical having from two to seven carbonatoms, e.g. about four to six carbon atoms, which radical may besubstituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxygroups or said alkylene or alkenylene may have one or more enchained oxoor imino radicals; B is a methyl radical or a cycloalkyl radical havingfrom three to seven carbon atoms, e.g. about five to six carbon atoms,or an aryl radical, selected from the group consisting of hydrocarbylaryl and heteroaryl radicals wherein the heteroatom is selected from thegroup consisting of nitrogen, oxygen and sulfur atoms; and X is selectedfrom the group consisting of cyano, --COOR, --CH₂ OR, --C(O)N(R₂), --CH₂N(R₂) --CH═N--OH and --CH₂ SR radicals, wherein R is hydrogen or C₁ toC₁₀ alkyl, phenyl or benzyl and E is O or S; or a pharmaceuticallyacceptable salt thereof. For example, A may be a straight chain alkyleneradical, e.g. heptylene, or alkenylene radical, e.g.3-hydroxy-1-heptylenyl, or an ethylenyloxyethylenyl radical or aminocarbonyl hydrazino methyl radical and B may be selected from the groupconsisting of methyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl,pyridyl, etc. B may also be substituted by radicals selected from thegroup consisting of halo, e.g. fluoro, chloro, iodo etc., nitro, amino,thiol, hydroxy, alkyloxy, alkylcarboxy, etc. Preferably, B is methyl,cyclohexyl or phenyl.

BRIEF DESCRIPTION OF THE DRAWINGS

The Drawing Figures outline the reaction scheme of the Example, below,wherein representative compounds of the invention, having either analkyl or alkenyl alpha chain are prepared and the numbered compounds areas described therein.

FIG. 1 outlines the reaction scheme of the Example wherein BIS-TES ether2, Aldehyde 3 and α, β-Unsaturated ester 4 are obtained.

FIG. 2 outlines the reaction scheme of the Example wherein Ester 5,Triol 6, Benzylester 7 and TBDMS Ether 8 are obtained.

FIG. 3 outlines the reaction scheme of the Example wherein Cycliccarbonate 9, 15-Hydroxybenzyl ester 10, Hydroxy Acid 11 and Diol 12 areobtained.

FIG. 4 outlines the reaction scheme of the Example wherein 2-AllylicAlcohol 13, t-Butyl Ester 14, Allyl Ester 15 and 15-TBDMS Ether 16 areobtained.

FIG. 5 outlines the reaction scheme of the Example wherein CyclicCarbonate 17, 15-Hydroxy Allyl Ester 18, 15-Hydroxy Acid 19 and Diol 20are obtained.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of the compounds of Formula I,above, as ocular hypotensives or a thromboxane ligands.

Preferably, the present invention relates to the use of a7-[carboxylalkyl or alkenyl]-6-[alkyl oralkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane or derivative thereof, e.g.an ester, hydroxyl, amino, amido, azido, oxime, thiol, ether or thiolether derivative as thromboxane ligands. These preferred therapeuticagents are represented by compounds having the formula II, ##STR5##

wherein A, B and X are as defined above.

For the purpose of this invention, unless further limited, the term"aliphatic" means linear and branched alkylene and alkenylene radicals,the terms "alkylene" and "alkenylene" mean divalent radicals derivedfrom alkanes and alkenes, respectively. The term "alkyl" refers to alkylgroups having from one to ten carbon atoms, the term "cycloalkyl" refersto cycloalkyl groups having from three to seven carbon atoms, the term"aryl" refers to aryl groups having from four to ten carbon atoms. Theterm "saturated or unsaturated acyclic hydrocarbon group" is used torefer to straight or branched chain, saturated or unsaturatedhydrocarbon groups having from one to about six, preferably one to aboutfour carbon atoms. Such groups include alkyl, alkenyl and alkynyl groupsof appropriate lengths, and preferably are alkyl, e.g. methyl, ethyl,propyl, butyl, pentyl, or hexyl, or an isomeric form thereof.

More preferably the method of the present invention comprisesadministering a 7-[carboxyalkyl or alkenyl]-6-[alkyl oralkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane derivative represented bythe formula III, ##STR6## wherein either the α or ω chain may beunsaturated, i.e. the dashed bonds represent a single bond or a doublebond which can be in the cis or trans configuration and R₃ is ═O, --OR₁or --O(CO)R₆ ; wherein R₁ is hydrogen or an alkyl radical having from 1to about 5 carbon atoms and R₆ is a saturated or unsaturated acyclichydrocarbon group having from 1 to about 20 carbon atoms, or --(CH₂)_(m)R₇ wherein m is 0-10, preferably 0-4; and R₇ is an aliphatic ring fromabout 3 to about 7 carbon atoms, or an aryl or heteroaryl ring, asdefined above; or a pharmaceutically acceptable salt thereof.

Preferably the derivative used in the above method of treatment is acompound of formula IV, ##STR7## wherein hatched lines indicate the αconfiguration and a solid triangle is used to indicate the βconfiguration.

As an aromatic ring, R₇ preferably is phenyl, and the heteroaromaticrings have oxygen, nitrogen or sulfur as a heteroatom, i.e., R₇ may bethienyl, furanyl, pyridyl, etc.

In a further aspect, the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formulae (I), (II), (III) or IV wherein the symbols have the abovemeanings, or a pharmaceutically acceptable salt thereof in admixturewith a non-toxic, pharmaceutically acceptable carrier or liquid vehicle.

Preferred representatives of the compounds within the scope of thepresent invention are the compounds of formula IV wherein X are --COOR,--CH₂ OH and --C(O)N(R)₂, wherein R is defined above, and thepharmaceutically acceptable salts thereof. Specific compounds within thescope of this invention are as follows:

Benzyl 7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-heptanoate

Allyl 7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-5Z-heptanoate

7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-heptanoic acid

7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-5Z-heptenoic acid

7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-5Z-hepten-1-ol

7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-heptan-1-ol

A pharmaceutically acceptable salt is any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Such salts are those formed withpharmaceutically acceptable cations, e.g., alkali metals, alkali earthmetals, amines, etc.

The compounds utilized in the method of the present invention can beprepared and administered in a wide variety of oral and parenteraldosage forms. Thus, the compounds of the present invention can beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, the compounds of the present invention can be administered byinhalation, for example, intranasally. Additionally, the compounds ofthe present invention can be administered transdermally. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of Formula I throughIV or a corresponding pharmaceutically acceptable salt of a compound ofFormula I through IV.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active compounds is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit: doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet cachet, orlozenge itself, or it can be the appropriate number of any of these inpackaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use, the compounds utilized in the method of thisinvention are administered at the initial dosage of about 0.01 mg toabout 10 mg/kg daily. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Pharmaceutical compositions for treating glaucoma or loweringintraocular pressure may be prepared by combining a therapeuticallyeffective amount of at least one compound according to the presentinvention, or a pharmaceutically acceptable salt thereof, as an activeingredient, with conventional ophthalmically acceptable pharmaceuticalexcipients, and by preparation of unit dosage forms suitable for topicalocular use. The therapeutically efficient amount typically is betweenabout 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0%(w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, an neutral pH being preferred but notessential. The formulations may also contain conventional,pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included i n the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, (sodium EDTA) although other chelating agents mayalso be used in place of or in conjunction with it.

The ingredients are usually used in the following amounts:

    ______________________________________                                        Ingredient        Amount (% w/v)                                              ______________________________________                                        active ingredient about 0.001-5                                               preservative      0-0.10                                                      vehicle           0-40                                                        tonicity adjustor 0-10                                                        buffer            0.01-10                                                     pH adjustor       q.s. pH 4.5-7.5                                             antioxidant       as needed                                                   surfactant        as needed                                                   purified water    as needed to make 100%                                      ______________________________________                                    

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses.

Especially preservative-free solutions are often formulated innon-resealable containers containing up to about ten, preferably up toabout five units doses, where a typical unit dose is from one to about 8drops, preferably one to about 3 drops. The volume of one drop usuallyis about 20-35 μl.

This invention is further illustrated by the following non-limitingexamples.

EXAMPLE

Bis-TES Ether 2.

A solution of the previously reported lactone 1 (7.41 g, 0.017 mol) inTHF (40 mL) was cooled to 0° C. and lithium aluminum hydride (21.0 mL ofa 1.0M solution in THF, 0.021 mol) was added dropwise. (See Corey, E.J.; Weinshanker, N. M.; Schaaf, T. K. and Huber, W. J. Am. Chem. Soc.,1969, 91, 5675.) After 2 h the reaction solution was poured into astirred mixture of ice-cold EtOAc/saturated aqueous NH₄ Cl. Theresultant mixture was stirred for 1 h and then extracted with EtOAc(2×). The combined organic portions were washed with brine, dried(MgSO₄), filtered and concentrated in vacuo to afford a clear, viscousoil.

The residue was diluted with DMF (90 mL) then 4-dimethylaminopyridine(595 mg, 0.005 mol) and imidazole (3.6 g, 0.052 mol) were added followedby chlorotriethylsilane (6.5 mL, 0.039 mol).

The reaction was stirred for 12 h, diluted with Et₂ O and washed with 1NHCl, water, saturated aqueous NaHCO₃ and brine. The organic portion wasdried (MgSO₄), filtered and concentrated in vacuo. Flash columnchromatography (silica gel, 19:1 hex/EtOAc) provided 11.24 g (99%) ofthe titled compound 2 as a clear, colorless oil.

Aldehyde 3.

Methyl sulfoxide (0.41 mL, 5.65 mmol) was added to a solution of oxalylchloride (1.4 mL of a 2.0 M solution in CH₂ Cl₂, 2.83 mmol) in CH₂ Cl₂(3.0 mL) at -70° C. After 10 minutes a solution of 2 (1.26 g, 1.88 mmol)in CH₂ Cl₂ (4.5 mL) as added and the reaction was stirred at -50° C. for2.5 h. The reaction solution was recooled to -70° C., triethylamine (1.2mL, 8.88 mmol) was added, and the reaction was allowed to warm to roomtemperature. Water was added and the mixture was extracted with EtOAc.The organic portion was washed with water, brine, dried (MgSO₄),filtered and concentrated in vacuo. FCC (silica gel, 9:1 hex/EtOAc)afforded 0.94 g (91%) of aldehyde 3.

α, β-Unsaturated Ester 4.

Potassium bis(trimethylsilyl)amide (11.1 mL of a 0.5M solution intoluene, 5.55 mmol) was added to a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl) phosphonate (1.77 g, 5.55mmol) and 18-crown-6(4.02 g, 15.2 mmol) in THF (20 mL) at -70° C. After0.5 h a solution of the aldehyde 3 (2.80 g, 5.07 mmol) in THF (10 mL)was added. The reaction was stirred at -70° C. for 2 h, warmed to 0° C.for 2 h and then quenched with saturated aqueous NH₄ Cl. After warmingto room temperature the mixture was extracted with EtOAc and the organicportion was washed with water (2×), brine, dried (MgSO₄), filtered andconcentrated in vacuo. FCC (silica gel, 8:1 hex/EtOAc) gave 2.22 g (70%)of pure cis-4 and 0.78 g (25%) of a mixture of cis-trans 4.

Ester 5.

Magnesium turnings (520 mg, 21.4 mmol) were added to a solution of 4(1.33 g, 2.14 mmol) in anhydrous MeOH (18 mL) at 23° C. After 12 h thereaction was quenched with 3N HCl, stirred 10 minutes and extracted withEt₂ O(2×). The combined organics were washed with saturated aqueousNaHCO₃ brine, dried (MgSO₄), filtered and concentrated in vacuo. FCC(9:1hex/EtOAc) gave 0.78 g (58%) of the saturated ester 5.

Triol 6.

A mixture of the ester 5 (0.78 g, 1.25 mmol) and lithium borohydride (55mg, 2.50 mmol) in anhydrous Et₂ O(5 mL) was stirred at 23° C. for 2 h.The reaction was quenched with 1N NaOH, stirred for 0.5 h and extractedwith EtOAc. The organic portion was washed with brine, dried (MgSO₄),filtered and concentrated in vacuo to afford the intermediate alcohol asa clear, colorless oil.

A mixture of the crude alcohol, tetrabutyl ammonium hydrogen sulfate(307 mg, 0.91 mmol) t-butyl bromoacetate (1.95 g, 9.98 mmol) and 25% w/waqueous NaOH (11.4 mL) in toluene (17.0 mL) was vigorously stirred at23° C. for 16 h. The reaction mixture was extracted with EtOAc (2×) andthe combined organics were washed with brine, dried (MgSO₄), filteredand concentrated in vacuo to give the intermediate ester as a clear,colorless oil.

Pyridinium p-toluenesulfonate (330 mg, 1.31 mmol) was added to asolution of the crude t-butyl ester in MeOH (7.5 mL) at 23° C. Afterstirring for 16 h the solvent was removed in vacuo. The residue wasdiluted with EtOAc and then washed with 1N HCl, saturated aqueousNaHCO₃, brine dried (MgSO₄), filtered and concentrated in vacuo, FCC(100% EtOAc), silica gel) provided 233.8 mg (60%) of triol 6.

Benzyl Eester 7.

A mixture of t-butyl ester 6 (320 mg, 0.77 mmol) and lithium hydroxide(3.0 mL of a 0.5N solution in H₂ O, 1.5 mmol) in THF (6.0 mL) was heatedto 55° C. for 2 h. The reaction was cooled to room temperature,acidified with 1N HCl and extracted with EtOAc (2×). The combinedorganics were washed with brine (2×), dried (MgSO₄), filtered andconcentrated in vacuo.

A solution of the residue and O-benzyl-N,N'-diisopropyl-isourea (910 mg,3.85 mmol) in benzene (8.0 mL) was heated to 60° C. for 12 h. Thesolvent was removed in vacuo and the residue was purified by FCC(silicagel, 100% EtOAc) to afford 343 mg (99%) of the benzyl ester 7 as aclear, viscous oil.

TBDMS Ether 8.

A solution of 7 (343 mg, 0.76 mmol) and phenyl boronic acid (103.3 mg,0.85 mmol) in CH₂ Cl₂ (4.5 mL) was heated to reflux for 12 h withazeotropic removal of water. The solution was cooled to 0° C. and2,6-lutidine (0.36 mL, 3.08 mmol) was added followed byt-butyldimethylsilyl trifluoromethane-sulfonate (0.53 mL, 2.31 mmol) inCH₂ Cl₂ (4.5 mL). After 12 h the solvent was removed in vacuo and theresidue was diluted with EtOAc. The organic portion was washed with 1NNaOH (2×), 1N HCl, brine, then dried (MgSO₄), filtered and concentratedin vacuo. FCC (silica gel, 2:1 hex/EtoAc) gave 137 mg (32%) of the silylether 8.

Cyclic Carbonate 9.

A solution of the diol (137 mg, 0.243 mmol) and pyridine (0.10 mL, 1.21mmol) in CH₂ Cl₂ (2.0 mL) was cooled to -70° C. Triphosgene (43.2 mg,0.145 mmol) in CH₂ Cl₂ (1.0 mL) was added and the reaction was allowedto warm to room temperature on its own accord. The reaction was quenchedwith saturated aqueous NH₄ Cl and extracted with EtOAc. The organicportion was washed with 1N HCl, saturated aqueous NaHCO₃, brine, dried(MgSO₄), filtered and concentrated in vacuo. FCC(silica gel, 3:1hex/EtOAc) afforded 68.3 mg (48%) of 9 as a colorless oil.

15-Hydroxybenzyl Ester 10.

Tetrabutylammonium fluoride (0.23 mL of a 1.0M solution in THF, 0.23mmol) was added to a solution of the silyl ether 9 (68 mg, 0.115 mmol)in THF (1.0 mL) at 23° C. After 2 h the reaction was diluted with EtOAcand washed with H₂ O, brine, dried (MgSO₄), filtered and concentrated invacuo. FCC (silica gel, 1:1 hex/EtOAc) provided 24.2 mg (44%) of alcohol10 as a viscous oil.

Hydroxy Acid 11.

A suspension of 10% by weight palladium on carbon (8 mg) and benzylester 10 (24 mg, 0.05 mmol) in 4:1 MeOH/1-methyl-1,4-cyclohexadiene(1.25 mL) was heated at 35-40° C. for 0.25 h. The reaction was dilutedwith EtOAc and filtered through celite. The filtrate was concentrated invacuo to give 34.1 mg (70%) of carboxylic acid 11.

Diol 12.

Lithium borohydride (60 mL of a 2.0M solution in THF, 0.12 mmol) wasadded to a solution of the benzyl ester 10 (60 mg, 0.13 mmol) inanhydrous Et₂ O (2.0 mL) cooled to 0° C. After 0.5 h the reaction wasquenched with 1N NaOH, warmed to room temperature and extracted withEtOAc. The organic portion was washed with brine, dried (MgSO₄),filtered and concentrated in vacuo. Purification by FCC (silica gel,100% EtOAc) have 32.8 mg (70%) of diol 12 as a clear, colorless oil.

2-Allylic Alcohol 13.

Diisobutylaluminum hydride (11.9 mL of a 1.0 M solution in toluene, 11.9mmol) was added to a solution of ene-ester 4 (2.46 g, 3.95 mmol) in THF(16 mL) at 0° C. After 2 h the reaction was quenched with MeOH (0.53 mL,13.0 mmol). The gelatinous mixture was warmed to room temperature,treated with 1N NaOH and stirred for 1 h. The resultant mixture wasextracted with EtOAc and the organic portion was washed with brine,dried (MgSO₄), filtered and concentrated in vacuo. FCC (silica gel, 2:1hex/EtOAc) gave 2.22 g (97%) of allylic alcohol 13.

t-Butyl Ester 14.

A mixture of the alcohol (1.5 g, 2.58 mmol), tetrabutylammonium hydrogensulfate (635, 9 mg, 1.87 mmol), 25% w/w aqueous NaOH (23.8 mL) andt-butyl bromoacetate (3.0 mL, 20.64) in toluene (35 mL) was stirredvigorously at 23° C. for 16 h. The reaction mixture was extracted withEtOAc (2×). The combined organics were washed with brine, dried (MgSO₄),filtered and concentrated in vacuo to give a clear, odorless oil.

A solution of the product obtained above and pyridinium p-toluenesulfonate (648.3 mg, 2.58 mmol) in MeOH (10.3 mL) was stirred at 23° C.for 16 h. The solvent was removed in vacuo and the residue was dilutedwith EtOAc then washed with 1N HCl, saturated aqueous NaHCO₃, and brine.The organic portion was dried (MgSO₄), filtered and concentrated invacuo. Purification by FCC (silica gel, 100% EtOAc) followed by 19:1EtOAc/MeOH) afforded 810 mg (76%) of trihydroxy t-butyl ester 14.

Allyl Ester 15.

A mixture of t-butyl ester 14 (1.01 g, 2.45 mmol) and lithium hydroxide(14.6 mL of a 0.5 N aqueous solution, 7.3 mmol) in THF (29 mL) wasstirred for 12 h at 23° C. The resultant solution was acidified with 1NHCl and extracted with EtOAc (2×). The combined organics were washedwith brine (2×), dried (MgSO₄), filtered and concentrated in vacuo.

The crude acid was diluted with acetone (10 mL) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.73 mL, 4.9 mmol) was addedfollowed by allyl bromide (0.85 mL, 9.8 mmol). After stirring for 16 hat 23° C. the solvent was removed in vacuo. The residue was diluted withEtOAc and washed with 1N NCl, saturated aqueous NaHCO₃ and brine. Theorganic portion was dried (MgSO₄), filtered and concentrated in vacuo.FCC (silica gel, 3:1 EtOAc/hexane) afforded 720 mg (74%) of the allylester 15 as a clear, colorless oil.

15-TBDMS Ether 16.

A solution of triol 15 (720 mg, 1.82 mmol) and phenyl boronic acid(243.9 mg, 2.0 mmol) in CH₂ Cl₂ (20 mL) was heated to flux withazeotropic removal of water. After 4 h the reaction was cooled to 0° C.and treated with 2,6-lutidine (0.85 mL, 7.27 mmol) followed byt-butyldimethylsilyl trifluoromethanesulfonate (1.3 mL, 5.45 mmol) andallowed to warm to room temperature. After 24 h the reaction wasquenched with 1N NaOH and stirred for 0.5 h. The mixture was dilutedwith EtOAc and washed with 10% aqueous NaOH (2×). The organic portionwas washed with 1N HCl, saturated aqueous NaHCO₃, brine then dried(MgSO₄), filtered and concentrated in vacuo. Purification of the residueby FCC (silica gel, 2:1 hex/EtOAC) provided 444 mg (48%) of silyl ether16.

Cyclic Carbonate 17.

A solution of triphosgene (155 mg, 0.52 mmol) in CH₂ Cl₂ (1.0 mL) wasadded the diol 16 (444 mg, 0.87 mmol) and pyridine (0.35 mL, 4.35 mmol)in CH₂ Cl₂ (6.0 mL) at -70° C. The reaction was allowed to warm to roomtemperature on its own accord and after 24 h it was quenched withsaturated aqueous NH₄ Cl. The resultant mixture was extracted withEtOAc. The organic portion was washed with 1N HCl, saturated aqueousNaHCO₃, brine, dried (MgSO₄), filtered and concentrated in vacuo.Purification by FCC (silica gel, 3:1 hex/EtOAc) gave 133.8 mg (29%) ofthe cyclic carbonate 17 as a light yellow oil.

15-Hydroxy Allyl Ester 18.

A solution of silyl ether 17 (133 mg, 0.25 mmol) and pyridiniump-toluenesulfonate (62.4 mg, 0.25 mmol) in MeOH (1.5 mL) was stirred at23° C. for 16 h. The solvent was removed in vacuo and the residue wasdiluted with EtOAc then washed with 1N HCl, saturated aqueous NaHCO₃ andbrine. The organic portion was dried (MgSO₄), filtered and concentratedin vacuo. Purification by FCC (silica gel, 1:1 hex/EtOAc) gave 70.8 mg(68%) of title compound 18 as a clear, colorless oil.

15-Hydroxy Acid 19.

Pyrrolidine (69 mL, 0.83 mmol) was added to a solution of allyl ester 18(35 mg, 0.083 mmol) and tetrakis-(triphenylphosphine)palladium(O) (9.6mg, 0.008 mmol) in CH₂ Cl₂ (1.5 mL) cooled to 0° C. After 15 minutes thereaction was diluted with EtOAc and washed with 1N HCl followed by brine(2×). The organic portion was dried (Na₂ SO₄), filtered and concentratedin vacuo. Purification through a Sep-Pak cartridge (silica gel, 3:1EtOAc/MeOH) afforded 27.0 mg (85%) of free acid 19.

Diol 20.

Lithium borohydride (41 mL, 0.083 mmol) was added to a solution of allylester (35 mg, 0.083 mmol) in anhydrous Et₂ O (1.5 mL) cooled to 0° C.After 0.5 h the reaction was quenched with 1N NaOH, warmed to roomtemperature and extracted with EtOAc. The organic portion was washedwith brine, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by FCC (silica gel, 100% EtOAc) to yield 21.5 mg(70%) of diol 20 as a clear, colorless oil.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent from one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same results. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

What is claimed is:
 1. A compound useful as a thromboxane ligand whichis a compound formula I, ##STR8## wherein Y is (CH₂)_(x) ; Z is selectedfrom the group consisting of OCH₂, ##STR9## and (CR₂)_(x), x is aninteger of 1 or 2; R₂ is hydrogen or an alkyl radical of from 1 to 4carbons, A is an alkylene or alkenylene radical having from two to sevencarbon atoms, which radical may be substituted with one or more hydroxy,oxo, alkyloxy or alkylcarboxy groups or said alkylene or alkenylene mayhave one or more enchained oxo or imino radicals; B is a methyl radicalor a cycloalkyl radical having from three to seven carbon atoms, or anaryl radical, selected from the group consisting of hydrocarbyl aryl andheteroaryl radicals wherein the heteroatom is selected from the groupconsisting of nitrogen, oxygen and sulfur atoms, or substitutedderivatives of said methyl, cycloalkyl or aryl radicals wherein saidsubstituent is selected from the group consisting of halo, nitro, amino,thiol, hydroxy, alkyloxy and alkylcarboxy; and X is selected from thegroup consisting of cyano, --COOR, --CH₂ OR, --C(O)N(R₂), --CH₂ N(R₂)--CH═N--OH and --CH₂ SR radicals, wherein R is hydrogen or a C₁ to C₁₀alkyl, phenyl or benzyl, and E is O or S; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 wherein saidcompound is a compound of formula II.
 3. A method of treating systemichypertension, pulmonary hypertension, myocardial ischemia, anginapectoris, coronary contraction, cerebrovascular contraction aftersubarachnoidal hemorrhage, hemorrhage and asthma which comprisesadministering to a mammal suffering therefrom a therapeuticallyeffective amount of a thromboxane ligand which is a compound formula I,##STR10## wherein Y is (CH₂)_(x) ; Z is selected from the groupconsisting of OCH₂, ##STR11## and (CR₂)_(x), x is an integer of 1 or 2;R₂ is hydrogen or an alkyl radical of from 1 to 4 carbons, A is analkylene or alkenylene radical having from two to seven carbon atoms,which radical may be substituted with one or more hydroxy, oxo, alkyloxyor alkylcarboxy groups or said alkylene or alkenylene may have one ormore enchained oxo or imino radicals; B is a methyl radical or acycloalkyl radical having from three to seven carbon atoms, or an arylradical, selected from the group consisting of hydrocarbyl aryl andheteroaryl radicals wherein the heteroatom is selected from the groupconsisting of nitrogen, oxygen and sulfur atoms, or substitutedderivatives of said methyl, cycloalkyl or aryl radicals wherein saidsubstituent is selected from the group consisting of halo, nitro, amino,thiol, hydroxy, alkyloxy and alkylcarboxy; and X is selected from thegroup consisting of nitro, cyano, --COOR, --CH₂ OR, --C(O)N(R₂), --CH₂N(R₂) --CH═N--OH and --CH₂ SR₁ radicals wherein R is hydrogen or a C₁ toC₁₀ alkyl, phenyl or benzyl and E is O or S; or a pharmaceuticallyacceptable salt thereof.
 4. The method of claim 3 wherein said compoundis a compound of formula II, ##STR12##
 5. A thromboxane ligandcomposition comprising, as its active ingredient, the compound of claim1 and a pharmaceutically-acceptable vehicle.
 6. A thromboxane ligandcomposition useful for treating systemic hypertension, pulmonaryhypertension, myocardial ischemia, angina pectoris, coronarycontraction, cerebrovascular contraction after subarachnoidalhemorrhage, hemorrhage and asthma comprising, as its active ingredient,the compound of claim 1 and a pharmaceutically acceptable vehicle.
 7. Amethod of treating ocular hypertension and glaucoma which comprisesadministering to a mammal suffering therefrom a therapeuticallyeffective amount of a thromboxane ligand which is a compound formula I,wherein Y is (CH₂)_(x) ; Z is selected from the group consisting of O,OCH₂, ##STR13## and (CR₂)_(x), x is an integer of 1 or 2; R₂ is hydrogenor an alkyl radical of from 1 to 4 carbons, A is an alkylene oralkenylene radical having from two to seven carbon atoms, which radicalmay be substituted with one or more hydroxy, oxo, alkyloxy oralkylcarboxy groups or said alkylene or alkenylene may have one or moreenchained oxo or imino radicals; B is a methyl radical or a cycloalkylradical having from three to seven carbon atoms, or an aryl radical,selected from the group consisting of hydrocarbyl aryl and heteroarylradicals wherein the heteroatom is selected from the group consisting ofnitrogen, oxygen and sulfur atoms, or substituted derivatives of saidmethyl, cycloalkyl or aryl radicals wherein said substituent is selectedfrom the group consisting of halo, nitro, amino, thiol, hydroxy,alkyloxy and alkylcarboxy; and X is selected from the group consistingof nitro, cyano, --COOR, --CH₂ OR, --C(O)N(R₂), --CH₂ N(R₂) --CH═N--OHand --CH₂ SR₁ radicals wherein R is hydrogen or a C₁ to C₁₀ alkyl,phenyl or benzyl and E is O or S; or a pharmaceutically acceptable saltthereof.
 8. The method of claim 7 wherein said compound is a compound offormula II, ##STR14##
 9. The method of claim 7 wherein said compound isa compound of formula IV, wherein the hatched line indicates the αconfiguration and the solid triangle indicates the β configuration. 10.The method of claim 7 wherein X is selected from the group consisting of--COOR, --CH₂ OR, --CH₂ N(R₂) and --C(O)N(R₂).
 11. The method of claim 9wherein said compound is selected from the group consisting ofBenzyl7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α, 4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-heptanoate Allyl7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-5Z-heptanoate7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-heptanoic acid7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-5Z-heptenoic acid7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-5Z-hepten-1-ol7-[7-(3α-Hydroxy-1E-octenyl)-3-oxo-2α,4α-dioxobicyclo[3.2.1]octan-6-yl]-2-oxa-heptan-1-ol.